Gastro-esophageal reflux disease (GERD) is by far the most common esophageal disorder, affecting more than one in ten adults over 40 years of age and one in four adults over 60. GERD may lead to the development of serious complications including ulcers, strictures, bleeding, columnar metaplasia (Barretts esophagus), and eventually adenocarcinoma of the esophagus. Preliminary data demonstrate that acid-induced inflammation of the esophagus begins with activation of acid sensitive vanilloid receptors (TRPV1) in the mucosa and synthesis of platelet aggregating factor (PAF) in the mucosal layer. PAF diffuses out of the mucosal layer causing production of hydrogen peroxide in leukocytes and production of IL-6 in circular muscle, where IL-6 causes production of additional hydrogen peroxide. We propose to focus on the onset of inflammation in response to acid in the esophageal lumen, i.e., on mechanisms responsible for acid-induced formation of PAF in the mucosal layer, and on mechanisms responsible for PAF/lL-6 -induced production of hydrogen peroxide in the circular muscle. We will test the hypothesis that: A) Acid in the esophageal lumen interacts with TRPV1 receptors present in the mucosal layer, leading to formation of PAF in the mucosal layer. B) PAF is released by the mucosal layer and interacts with leukocytes and with circular muscle, inducing production of H2O2 by activation of NADPH oxidase in leukocytes, and inducing production of IL-6 in circular muscle, where IL-6 activates a phagocytic-like NADPH oxidase, producing H2O2. C) H2O2 is present in the the mucosal layer after induction of experimental esophagitis, but not after short-term exposure to acid. To explain this change we propose that PAF is produced in the mucosa in the initial response to acid. PAF is released from the mucosa inducing production of H2O2 by muscle and white blood cells. H2O2 in turn, may upregulate mucosa NADPH oxidase, causing delayed production of H2O2 in the mucosa. We have demonstrated that scavenging H202 reverses some of the motor changes observed in esophagitis, pointing to ROS as an important mediator of dysmotility. Understanding the mechanisms responsible for overproduction of H2O2 may help in devising novel therapeutic approaches focused on restoring normal esophageal and LES function that are not always improved by acid suppression therapy.